Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci

Converging evidence implicates immune abnormalities in schizophrenia (SCZ), and recent genome-wide association studies (GWAS) have identified immune-related single-nucleotide polymorphisms (SNPs) associated with SCZ. Using the conditional false discovery rate (FDR) approach, we evaluated pleiotropy in SNPs associated with SCZ (n=21 856) and multiple sclerosis (MS) (n=43 879), an inflammatory, demyelinating disease of the central nervous system. Because SCZ and bipolar disorder (BD) show substantial clinical and genetic overlap, we also investigated pleiotropy between BD (n=16 731) and MS. We found significant genetic overlap between SCZ and MS and identified 21 independent loci associated with SCZ, conditioned on association with MS. This enrichment was driven by the major histocompatibility complex (MHC). Importantly, we detected the involvement of the same human leukocyte antigen (HLA) alleles in both SCZ and MS, but with an opposite directionality of effect of associated HLA alleles (that is, MS risk alleles were associated with decreased SCZ risk). In contrast, we found no genetic overlap between BD and MS. Considered together, our findings demonstrate genetic pleiotropy between SCZ and MS and suggest that the MHC signals may differentiate SCZ from BD susceptibility.Molecular Psychiatry advance online publication, 28 January 2014; doi:10.1038/mp.2013.195.

The effects of consistency and inconsistency between attentional focus and task objective in learning a golf putting task

Converging evidence has demonstrated learning advantages when an individual is instructed to focus their attention externally. However, many of the motor tasks utilized in past research had clear external objectives (i.e., putting accuracy), creating a compatible relationship between an external focus of attention (i.e., outcome) and an external task objective (i.e., putting accuracy). The present study examined whether or not the consistency of instructions and task objective would differentially impact the acquisition of a golf putting task. Participants performed a putting task in a control condition or in one of four experimental conditions resulting from the factorial interaction of task instructions (internal or external) and task objective (internal or external). The retention and transfer data revealed that participants who received an external task objective demonstrated superior outcome scores. Participants who received technique information paired with outcome information demonstrated superior technique scores.

Coding of visual space during motor preparation: approaching objects rapidly modulate corticospinal excitability in hand-centered coordinates

Defensive behaviors, such as withdrawing your hand to avoid potentially harmful approaching objects, rely on rapid sensorimotor transformations between visual and motor coordinates. We examined the reference frame for coding visual information about objects approaching the hand during motor preparation. Subjects performed a simple visuomanual task while a task-irrelevant distractor ball rapidly approached a location either near to or far from their hand. After the distractor ball appearance, single pulses of transcranial magnetic stimulation were delivered over the subject's primary motor cortex, eliciting motor evoked potentials (MEPs) in their responding hand. MEP amplitude was reduced when the ball approached near the responding hand, both when the hand was on the left and the right of the midline. Strikingly, this suppression occurred very early, at 70-80ms after ball appearance, and was not modified by visual fixation location. Furthermore, it was selective for approaching balls, since static visual distractors did not modulate MEP amplitude. Together with additional behavioral measurements, we provide converging evidence for automatic hand-centered coding of visual space in the human brain.

Searching for happiness across cultures

Three experiments examined the cultural relativity of emotion recognition using the visual search task. Caucasian-English and Japanese participants were required to search for an angry or happy discrepant face target against an array of competing distractor faces. Both cultural groups performed the task with displays that consisted of Caucasian and Japanese faces in order to investigate the effects of racial congruence on emotion detection performance. Under high perceptual load conditions, both cultural groups detected the happy face more efficiently than the angry face. When perceptual load was reduced such that target detection could be achieved by feature-matching, the English group continued to show a happiness advantage in search performance that was more strongly pronounced for other race faces. Japanese participants showed search time equivalence for happy and angry targets. Experiment 3 encouraged participants to adopt a perceptual based strategy for target detection by removing the term 'emotion' from the instructions. Whilst this manipulation did not alter the happiness advantage displayed by our English group, it reinstated it for our Japanese group, who showed a detection advantage for happiness only for other race faces. The results demonstrate cultural and linguistic modifiers on the perceptual saliency of the emotional signal and provide new converging evidence from cognitive psychology for the interactionist perspective on emotional expression recognition.

Mental concerts: Musical imagery and auditory cortex

Most people intuitively understand what it means to “hear a tune in your head.” Converging evidence now indicates that auditory cortical areas can be recruited even in the absence of sound and that this corresponds to the phenomenological experience of imagining music. We discuss these findings as well as some methodological challenges. We also consider the role of core versus belt areas in musical imagery, the relation between auditory and motor systems during imagery of music performance, and practical implications of this research.

Integration of electrical neuroimaging with other functional imaging methods

Integrating evidence from different imaging modalities is important to overcome specific limitations of any given imaging method, such as insensitivity of the EEG to unsynchronized neural events, or the lack of fMRI sensitivity to events of low metabolic demand. Processes that are visible in one modality may be related in a nontrivial way to other processes visible in another modality and insight may only be obtained by integrating both methods through a common analysis. For example, brain activity at rest seems to be at least partly determined by an interaction of cortical rhythms (visible to EEG but not to fMRI) with sub-cortical activity (visible to fMRI, but usually not to EEG without averaging). A combination of EEG and fMRI data during rest may thus be more informative than the sum of two separate analyses in both modalities. Integration is also an important source of converging evidence about specific aspects and general principles of neural functions and their dysfunctions in certain pathologies. This is because not only electrical, but also energetic, biochemical, hemodynamic and metabolic processes characterize neural states and functions, and because brain structure provides crucial constraints upon neural functions. Focusing on multimodal integration of functional data should not distract from the privileged status of the electric field as the primary direct, noninvasive real-time measure of neural transmission. The preceding chapters illustrate how electrical neuroimaging has turned scalp EEG into an imaging modality which directly captures the full temporal dynamics of neural activity in the brain.

Dementia with lewy bodies--diagnosis and treatment

Dementia with Lewy bodies (DLB) accounts for 15-20% of all autopsy confirmed dementias in old age. Characteristic histopathological changes are intracellular Lewy bodies and Lewy neurites, with abundant senile plaques but sparse neurofibrillary tangles. Core clinical features are fluctuating cognitive impairment, persistent visual hallucinations and extrapyramidal motor symptoms (parkinsonism). One of these core features has to be present for a diagnosis of possible DLB, and two for probable DLB. Supportive features are repeated falls, syncope, transient loss of consciousness, neuroleptic sensitivity, delusions and hallucinations in other modalities. DLB is clinically under-diagnosed and frequently misclassified as systemic delirium or dementia due to Alzheimer's disease or cerebrovascular disease. Therapeutic approaches to DLB can pose difficult dilemmas in pharmacological management. Neuroleptic medication is relatively contraindicated because some patients show severe neuroleptic sensitivity, which is associated with increased morbidity and mortality. Antiparkinsonian medication has the potential to exacerbate psychotic symptoms and may be relatively ineffective at relieving extrapyramidal motor symptoms. Recently there is converging evidence that treatment with cholinesterase inhibitors can offer a safe alternative for the symptomatic treatment of cognitive and neuropsychiatric features in DLB. This review will focus on the clinical characteristics of DLB, its differential diagnosis and on possible management strategies.

Change Detection Memory in Rhesus Monkeys and Humans

Visual short-term memory (VSTM) is the storage of visual information over a brief time period (usually a few seconds or less). Over the past decade, the most popular task for studying VSTM in humans has been the change detection task. In this task, subjects must remember several visual items per trial in order to identify a change following a brief delay interval. Results from change detection tasks have shown that VSTM is limited; humans are only able to accurately hold a few visual items in mind over a brief delay. However, there has been much debate in regard to the structure or cause of these limitations. The two most popular conceptualizations of VSTM limitations in recent years have been the fixed-capacity model and the continuous-resource model. The fixed-capacity model proposes a discrete limit on the total number of visual items that can be stored in VSTM. The continuous-resource model proposes a continuous-resource that can be allocated among many visual items in VSTM, with noise in item memory increasing as the number of items to be remembered increases. While VSTM is far from being completely understood in humans, even less is known about VSTM in non-human animals, including the rhesus monkey (Macaca mulatta). Given that rhesus monkeys are the premier medical model for humans, it is important to understand their VSTM if they are to contribute to understanding human memory. The primary goals of this study were to train and test rhesus monkeys and humans in change detection in order to directly compare VSTM between the two species and explore the possibility that direct species comparison might shed light on the fixed-capacity vs. continuous-resource models of VSTM. The comparative results suggest qualitatively similar VSTM for the two species through converging evidence supporting the continuous-resource model and thereby establish rhesus monkeys as a good system for exploring neurophysiological correlates of VSTM.

What constitutes vulnerable self-esteem? Comparing the prospective effects of low, unstable, and contingent self-esteem on depressive symptoms

A growing body of longitudinal studies suggests that low self-esteem is a risk factor for depression. However, it is unclear whether other characteristics of self-esteem, besides its level, explain incremental or even greater variance in subsequent depression. We examined the prospective effects of self-esteem level, instability (i.e., the degree of variability in self-esteem across short periods), and contingency (i.e., the degree to which self-esteem fluctuates in response to self-relevant events) on depressive symptoms in 1 overarching model, using data from 2 longitudinal studies. In Study 1, 372 adults were assessed at 2 waves over 6 months, including 40 daily diary assessments at Wave 1. In Study 2, 235 young adults were assessed at 2 waves over 6 weeks, including about 6 daily diary assessments at each wave. Self-esteem contingency was measured by self-report and by a statistical index based on the diary data (capturing event-related fluctuations in self-esteem). In both studies self-esteem level, but not self-esteem contingency, predicted subsequent depressive symptoms. Self-esteem instability predicted subsequent depressive symptoms in Study 2 only, with a smaller effect size than self-esteem level. Also, level, instability, and contingency of self-esteem did not interact in the prediction of depressive symptoms. Moreover, the effect of self-esteem level held when controlling for neuroticism and for all other Big Five personality traits. Thus, the findings provide converging evidence for a vulnerability effect of self-esteem level, tentative evidence for a smaller vulnerability effect of self-esteem instability, and no evidence for a vulnerability effect of self-esteem contingency.

The effect of pain on involuntary and voluntary capture of attention

BACKGROUND: There is converging evidence for the notion that pain affects a broad range of attentional domains. This study investigated the influence of pain on the involuntary capture of attention as indexed by the P3a component in the event-related potential derived from the electroencephalogram. METHODS: Participants performed in an auditory oddball task in a pain-free and a pain condition during which they submerged a hand in cold water. Novel, infrequent and unexpected auditory stimuli were presented randomly in a series of frequent standard and infrequent target tones. P3a and P3b amplitudes were observed to novel, unexpected and target-related stimuli, respectively. RESULTS: Both electrophysiological components were characterized by reduced amplitudes in the pain compared with the pain-free condition. Hit rate and reaction time to target stimuli did not differ between the two conditions presumably because the experimental task was not difficult enough to exceed attentional capacities under pain conditions. CONCLUSIONS: These results indicate that voluntary attention serving the maintenance and control of ongoing information processing (reflected by the P3b amplitude) is impaired by pain. In addition, the involuntary capture of attention and orientation to novel, unexpected information (measured by the P3a) is also impaired by pain. Thus, neurophysiological measures examined in this study support the theoretical positions proposing that pain can reduce attentional processing capacity. These findings have potentially important implications at the theoretical level for our understanding of the interplay of pain and cognition, and at the therapeutic level for the clinical treatment of individuals experiencing ongoing pain.

Tracking memory's trace

There is strong converging evidence that the intermediate and medial part of the hyperstriatum ventrale of the chick brain is a memory store for information acquired through the learning process of imprinting. Neurons in this memory system come, through imprinting, to respond selectively to the imprinting stimulus (IS) neurons and so possess the properties of a memory trace. Therefore, the responses of the intermediate and medial part of the hyperstriatum ventrale neurons to a visual imprinting stimulus were determined before, during, and after training. Of the total recorded population, the proportions of IS neurons shortly after each of two 1-h training sessions were significantly higher (approximately 2 times) than the pretraining proportion. However, ≈4.5 h later this proportion had fallen significantly and did not differ significantly from the pretraining proportion. Nevertheless, ≈21.5 h after the end of training, the proportion of IS neurons was at its highest (approximately 3 times the pretraining level). No significant fluctuations occurred in the proportions of neurons responding to the alternative stimulus. In addition, nonmonotonic changes were found commonly in the activity of 230 of the neurons tracked individually from before training to shortly after the end of training. Thus the pattern of change in responsiveness both at the population level and at the level of individual neurons was highly nonmonotonic. Such a pattern of change is not consistent with simple models of memory based on synaptic strengthening to asymptote. A model is proposed that accounts for the changes in the population responses to the imprinting stimulus in terms of changes in the responses of individual neurons.

Illusory memories: A cognitive neuroscience analysis

Memory illusions and distortions have long been of interest to psychology researchers studying memory, but neuropsychologists and neuroscientists have paid relatively little attention to them. This article attempts to lay the foundation for a cognitive neuroscience analysis of memory illusions and distortions by reviewing relevant evidence from a patient with a right frontal lobe lesion, patients with amnesia produced by damage to the medial temporal lobes, normal aging, and healthy young volunteers studied with functional neuroimaging techniques. Particular attention is paid to the contrasting roles of prefrontal cortex and medial temporal lobe structures in accurate and illusory remembering. Converging evidence suggests that the study of illusory memories can provide a useful tool for delineating the brain processes and systems involved in constructive aspects of remembering.

Cognitive modelling and the behaviour genetics of reading

While it is well known that reading is highly heritable, less has been understood about the bases of these genetic influences. In this paper, we review the research that we have been conducting in recent years to examine genetic and environmental influences on the particular reading processes specified in the dual-route cognitive model of reading. We argue that a detailed understanding of the role of genetic factors in reading acquisition requires the delineation and measurement of precise phenotypes, derived from well-articulated models of the reading process. We report evidence for independent genetic influences on the lexical and nonlexical reading processes represented in the dual-route model, based on studies of children with particular subtypes of dyslexia, and on univariate and multivariate genetic modelling of reading performance in the normally reading population.

Histaminergic modulation in Tourette syndrome

Introduction: Tourette syndrome is a neurodevelopmental disorder characterized by multiple motor tics and at least one vocal/phonic tic. Clinical phenotypes show a wide variability, often incorporating behavioral symptoms. The exact pathophysiology of Tourette syndrome is unknown, however genetic vulnerability and alterations in dopaminergic neurotransmission have consistently been reported. Other biochemical pathways, including histaminergic neurotransmission, are likely to be involved but have received relatively little attention until recently. Areas covered: We conducted a systematic literature review focusing on the role of histaminergic neurotransmission and its pharmacological modulation in Tourette syndrome. We identified a number of relevant original studies published over the last five years, mainly focusing on genetic aspects. Expert opinion: There is converging evidence from recent studies supporting the hypothesis that histaminergic neurotransmission may play a role in the pathophysiology of Tourette syndrome. Most studies focused on the role of the histidine decarboxylase gene and the potential usefulness of histidine decarboxylase knockout mice as an experimental model for studying neurochemical function in Tourette syndrome. There have been no large scale studies assessing the use of histaminergic medications in the management of Tourette syndrome. This would be an important area for future research, with direct implications for the clinical management of selected phenotypes.